1. Field of the Invention
This invention relates to a topical anesthetic formulation comprising lidocaine and a volatile carrier/penetration enhancer. The formulation markedly enhances the delivery rate of the anesthetic, can be administered in a simple manner, and is free of side effects associated with many penetration enhancers. More particularly, the invention concerns a method of anesthetizing by using such a formulation.
2. Description of the Related Art
Historically, dermal anesthesia for minor skin surgery has been achieved by the injection of anesthetic solution via a needle and syringe. Although this technique is effective, it suffers from several drawbacks. Many patients, especially children, do not tolerate the pain of an injection well. Also, injection of topical anesthetic into an allergic patient could result in a severe reaction.
The state of the art shows an increase in the use of topical anesthetic over injected anesthetics. Topical anesthetics act via a loss of sensation in the localized area of administration in the body. The mechanism by which topical anesthetics induce their effect, while not having been determined definitively, is generally thought to be based upon the ability to topically interfere with the initiation and transmission of a nerve impulse, e.g., interfering with the initiation and/or propagation of a depolarization wave in a localized area of nerve tissue.
In recent years, creams containing a Eutectic Mixture of Local Anesthetics (EMLA®) such as lidocaine and prilocaine have been found useful as a topical anesthetic for superficial skin procedures. The EMLA® cream is applied to a lesion and adjacent tissue and covered with an occlusive dressing for about 20 minutes to about 2 hours. More recently, a formulation of 30% lidocaine in an acid mantle cream has been found to be an effective and inexpensive topical anesthetic.
While the EMLA® and topical lidocaine creams are welcome alternatives to anesthetic injection, they have several drawbacks. A major inconvenience is that local anesthesia of intact skin for minor procedures is not achieved until at least 60 minutes following application. For more invasive procedures, such as split skin graft harvesting, at least two hours may be required. This delay in onset is a significant disadvantage, as it is a great inconvenience for both patients and medical staff. Such delay is particularly a problem in the area of pediatrics, where any additional time spent awaiting treatment only contributes to the anxiety of the patient.
Another disadvantage with EMLA® cream is that, for deep penetrative effect, it is necessary that the cream be applied under an occlusive dressing. Specifically, a bilayer of laminate and absorbent cellulose is taped to the area of the skin to be anesthetized. Such a dressing is inconvenient and messy.
Skin is a structurally complex, relatively thick membrane. Molecules moving from the environment into and through intact skin must first penetrate the stratum corneum and any material on its surface. They must then penetrate the viable epidermis, the papillary dermis, and the capillary walls into the blood stream or lymph channels to be so absorbed; molecules must overcome a different resistance to penetration in each type of tissue. Transport across the skin membrane is thus a complex phenomenon. However, it is the cells of the stratum corneum, which present the primary barrier to absorption of topical compositions or transdermally administered drugs.
This impermeability may be attributed to the nature of one very thin layer created by normal development and physiological changes in the skin. After cells are formed in the basal layer, they begin to migrate toward the skin surface, until they are eventually sloughed off. As they undergo this migration, they become progressively more dehydrated and keratinized. When they reach the surface, just prior to being discarded, they form a thin layer of dense, metabolically inactive cells approximately ten microns (10-15 cells) thick, the stratum corneum or “cornified layer.” As a result of the high degree of keratinization of the cells, which comprise the stratum corneum, a formidable barrier is created. Absorption through a mucosal surface is generally efficient because the stratum corneum is absent. Therefore, any formulation to be utilized as an efficient topical, transdermal anesthetic must be capable of being readily absorbed through the skin.
In addition to the thickness and integrity of the stratum corneum epidermis, percutaneous or transdermal absorption can significantly alter drug kinetics and depend on a variety of factors including site of application, size of active drug molecule, permeability of the membrane of the transdermal drug delivery system, state of skin hydration, pH of the drug, drug metabolism by skin flora, lipid solubility, and alteration of blood flow in the skin by additives and body temperature.
To increase the rate of penetration of drugs across the skin, the prior art shows the use of various skin penetration enhancers. Currently available percutaneous and transmucosal penetration enhancers use solvents or detergents to alter the physical properties of the multilayered lipid bilayers. Such agents include dimethylsulfoxide (DMSO), oleyl alcohol (OA), propylene glycol (PG), methyl pyrrolidone and AZONE® (dodecylazyl cycloheptan 2-one). However, unfortunately, the uses of the known penetration enhancers are associated with disadvantages.
For one, the penetration enhancer is typically co-administered with the desired drug. That is, the penetration enhancer passes through the patient's skin at the same time the drug does. Depending upon the exact nature of the penetration enhancer, this can lead to side effects related directly to the penetration enhancers.
Another disadvantage is that the addition of penetration enhancers tends to change the concentration of the drug, which presents the problem of difficulties in achieving an acceptable delivery rate of the medicament that needs to be delivered through the skin.
Another disadvantage is that the enhancers are often organic solvents, which can, in some cases, react with and alter the character of the drug being delivered. In addition, the enhancers can interact with the patient's skin, in some cases causing irritation and the like.
U.S. Pat. No. 5,415,866 entitled “Topical Drug Delivery System” to Zook discloses a topical anesthetic including a eutectic mixture of lidocaine and prilocaine and a high amount of alcohol. The Zook reference teaches the use of an occlusive dressing to prevent the desiccation of the drug. A disadvantage of the Zook invention is that the alcohol is co-administered with the drug and passes through the patient's skin at the same time the drug does, which can lead to side effects or, in the case of adulterated alcohol, discomfort. Another disadvantage is that the alcohol can interact with the patient's skin for extended periods and cause irritation and the like. Another disadvantage associated with the use of an occlusive dressing is that the drug is applied “under cover” and gives no direct stimulus to the patient. It is difficult for the patient to know when or if the anesthetic is taking effect. Further, without some form of psychological stimulus, the patient may not become mentally receptive to becoming anesthetized.
Further representing the state of the art is U.S. Pat. No. 5,993,836, owned by the same inventor, which is incorporated herein by reference. The patent discloses a topical anesthetic formulation including, e.g., lidocane (15%), prilocane (5%), and dibucaine (0.75%) as anesthetics; phenylephrine as vasoconstrictor; and a lipophilic base. Lidocane and prilocane form a eutectic mixture, and the formulation is incorporated in a lipophilic base. While representing an improvement over prior art topical anesthetic formulations, there remains a need for further improvement in delivery rate of the anesthetic, ease of administration, and patient acceptance.